EP2235000B1 - Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage - Google Patents

Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage Download PDF

Info

Publication number
EP2235000B1
EP2235000B1 EP09700499.8A EP09700499A EP2235000B1 EP 2235000 B1 EP2235000 B1 EP 2235000B1 EP 09700499 A EP09700499 A EP 09700499A EP 2235000 B1 EP2235000 B1 EP 2235000B1
Authority
EP
European Patent Office
Prior art keywords
benzamide
phenylamino
methoxy
methyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP09700499.8A
Other languages
German (de)
English (en)
Other versions
EP2235000A2 (fr
Inventor
Jamal Tazi
David Grierson
Florence Mahuteau-Betzer
Pierre Roux
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Universite de Montpellier I
Institut Curie
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universite de Montpellier I
Institut Curie
Universite de Montpellier
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Universite de Montpellier I, Institut Curie, Universite de Montpellier filed Critical Centre National de la Recherche Scientifique CNRS
Priority to EP19164367.5A priority Critical patent/EP3536691B1/fr
Priority to PL09700499T priority patent/PL2235000T3/pl
Publication of EP2235000A2 publication Critical patent/EP2235000A2/fr
Application granted granted Critical
Publication of EP2235000B1 publication Critical patent/EP2235000B1/fr
Priority to HRP20201369TT priority patent/HRP20201369T1/hr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/06—Anabolic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/80—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention relates to novel indole derivative compounds for the preparation of compositions useful for the treatment of diseases resulting from changes in splicing processes.
  • indole derivative compounds such as ellipticine derivatives and aza-ellipticine derivatives are already known as intercalating molecules for correcting dysfunctions in gene expression, notably in DNA replication. They have been more specifically described for treating diseases such as cancer, leukemia or AIDS (see in particular patents FR 2,627,493 , FR 2,645,861 , FR 2,436,786 ).
  • NRTIs nucleosidic
  • NRTIs non-nucleosidic
  • PIs protease inhibitors
  • anti-retroviral compound used for its ability to prevent viruses from entering the cell.
  • entry inhibitors can be either peptides that interfere with the fusion of viral glycoproteins gp41 or gp120 with the membrane of CD4 cells or molecules that target HIV cellular co-receptors CCR5 and CXCR4.
  • the absence of cellular proteins resembling HIV integrase has also been exploited to develop novel anti-HIV molecules that inhibit this enzymatic activity.
  • integrase inhibitors are in the clinical trial phase, no molecule is yet available on the market.
  • Duchenne muscular dystrophy is a serious illness resulting from mutations in the dystrophin gene. The absence of this protein leads to degeneration of skeletal and cardiac muscles.
  • exon skipping Several therapeutic strategies are currently envisaged, including so-called exon skipping, whose principle is to cut from dystrophin the internal exon carrying the mutation, thus allowing the production of a shorter but functional dystrophin.
  • Laminopathies are disorders that lead to an unsatisfactory quality of life, require expensive care and, in many cases, can lead to premature death (i.e., laminopathies of striated muscle tissues and laminopathies characterized by premature aging). Laminopathies are caused by functional changes in lamins, ubiquitous proteins located in the cell nucleus, and in their molecular partners. Most cases of progeria, or early-aging syndrome, are caused by a recurring de novo point mutation (c.1824C>T, "G608G”) occurring in exon 11, i.e., in the part of the gene specifically coding for lamin A.
  • the splicing process plays a key role.
  • This intracellular splicing process consists of eliminating introns in pre-messenger RNAs to produce mature messenger RNAs that can be used by the translation mechanism of the cell ( SHARP, Cell, vol. 77, p. 805-815, 1994 ).
  • the same precursor can be the source of messenger RNAs coding for proteins with distinct functions ( BLACK, Annu. Rev. Biochem. vol. 72, p. 291-336, 2003 ).
  • the precise selection of 5' and 3' splicing sites is thus a mechanism that generates diversity and that can lead to the regulation of gene expression according to the type of tissue or during the development of an organism.
  • SR RNA recognition motifs
  • RISPR RNA recognition motifs
  • RS domain a domain rich in arginine and serine residues
  • ESE exonic splicing enhancer
  • ISE intronic splicing enhancer
  • SR proteins are able to activate, in a dose-dependant manner, sub-optimal splicing sites and to enable the inclusion of exons ( GRAVELEY, RNA, vol. 6, p. 1197-1211, 2000 ).
  • ESE exonic splicing enhancer
  • ISE intra splicing enhancer
  • GRAVELEY RNA, vol. 6, p. 1197-1211, 2000
  • the activity of an SR protein in alternative splicing is specific insofar as the inactivation of the corresponding gene is lethal ( WANG et al., Mol. Cell, vol. 7, p. 331-342, 2001 ).
  • mutations can interfere with splicing by inactivating or creating splicing sites, but also by modifying or generating regulating elements such as splicing enhancers or splicing silencers in a particular gene ( CARTEGNI et al., Nat. Rev. Genet., vol. 3, p. 285-298, 2002 ; TAZI et al., TIBS, vol. 40, p. 469-478, 2005 ).
  • the compounds described have a flat structure with four rings that have the disadvantage of intercalating between DNA bases and can thus lead to cellular toxicity.
  • a first object of the invention relates to one of the following compounds:
  • a second object of the invention consists of a pharmaceutical composition comprising at least one compound as described above and, optionally, a pharmaceutically acceptable support.
  • the composition can include emulsions, microemulsions, oil in water emulsions, anhydrous lipids and water in oil emulsions or other types of emulsions.
  • the inventive composition can further include one or more additives such as diluents, excipients, stabilizers and preservatives.
  • additives are well known to those skilled in the art and are described notably in “ Ullmann's Encyclopedia of Industrial Chemistry, 6th Ed.” (various editors, 1989-1998, Marcel Dekker ) and in “ Pharmaceutical Dosage Forms and Drug Delivery Systems” (ANSEL et al., 1994, WILLIAMS & WILKINS ).
  • a third object consists of the use of at least one compound as described above in preparing a drug to treat, in a subject, a disease resulting from at least one splicing anomaly.
  • the term "subject” refers to a mammal such as a rodent, cat, dog, primate or human, preferably said subject is a human.
  • the inventive compounds have the ability to inhibit pre-messenger RNA splicing processes that are either constitutive or, more specifically, dependent on regulating sequences known as an ESE (exonic splicing enhancer), ISE (intronic splicing enhancer), ESS (exonic splicing silencer) and ISS (intronic splicing silencer).
  • ESE exonic splicing enhancer
  • ISE intra splicing enhancer
  • ESS exonic splicing silencer
  • ISS intra splicing silencer
  • splicing processes are either constitutive and/or or dependent on ESE regulating sequences.
  • Diseases related to the splicing process include genetic diseases resulting from the alteration of splicing processes, most notably Frasier syndrome, frontotemporal dementia related to chromosome 17 (a form of Parkinson's), Leigh syndrome (a type of encephalopathy), atypical cystic fibrosis, certain neuropathologies including most notably Alzheimer's related to a mutation of the Tau protein, amyotrophy which affects the SMN (survival motor neuron) gene, depression related to dysregulation of serotonin splicing, and certain metastatic cancers in which the overall splicing process is affected (most notably in epithelial cancer including breast cancer, colon cancer, pancreas cancer, liver cancer, prostate cancer, uterus cancer and certain lymphomas).
  • Frasier syndrome a form of Parkinson's
  • Leigh syndrome a type of encephalopathy
  • cystic fibrosis certain neuropathologies including most notably Alzheimer's related to a mutation of the Tau protein, amyotrophy which affects the
  • the use of the at least one compound of the invention is for preparing a drug to treat, in a subject, a cancer, most preferably a metastatic cancer, which cancer is selected in the group comprising breast cancer, colon cancer, pancreas cancer, liver cancer, prostate cancer, uterus cancer.
  • anomalies play a role in the appearance of pathologies with aging.
  • diseases that appear with aging and that are likely related to the splicing process include atherosclerosis, insulin resistant type II diabetes, cataracts, osteoporosis and aging of the skin.
  • Diseases related to the splicing process also include diseases of viral origin for which ESE sequences are identified for splicing.
  • diseases of viral origin is AIDS.
  • the use of the at least one compound of the invention is for preparing a drug to treat, in a subject, diseases of viral origin for which ESE sequences are identified for splicing, preferably AIDS.
  • DMD Duchenne muscular dystrophy
  • the use of the at least one compound of the invention is for preparing a drug to treat, in a subject, diseases associated with gene mutations which may be treated by exon skipping, preferably Duchenne muscular dystrophy (DMD).
  • diseases associated with gene mutations which may be treated by exon skipping, preferably Duchenne muscular dystrophy (DMD).
  • DMD Duchenne muscular dystrophy
  • the disease related to a splicing anomaly is selected among the group comprising AIDS, cancer, Leigh syndrome characterized by a mitochondrial defect, early-aging syndrome (progeria) and Duchenne muscular dystrophy.
  • a fourth object of the invention relates to a therapeutic method for treating a subject for a genetic disease resulting from splicing anomalies comprising the administration of a therapeutically effective quantity of a pharmaceutical composition as described above.
  • a “therapeutically effective quantity” means a quantity that induces inhibition of the splicing of the pre-mRNAs of interest. Those skilled in the art will be able to determine said therapeutically effective quantity based on their general knowledge and on the methods described in the examples.
  • the compounds can be administered by any mode of administration such as, for example, by intramuscular, intravenous or oral route, etc.
  • said composition further includes an excipient making it possible to formulate the inventive compounds in such a way that said composition is provided in solid or liquid form to be prepared and administered by intravenous route.
  • the inventive compounds preferably will be administered by intravenous route at a concentration of 80-100 mg/m 2 .
  • concentration will be chosen by those skilled in the art according to the organ or tissue to be treated, the state of advancement of the disease and the targeting mode used.
  • compound IDC16 (BAKKOUR et al ., cited above, 2007) interacts functionally with the SF2/ASF complex and thus contributes to blocking alternative splicing during HIV replication, leading to the termination of the production of Tat protein.
  • the inventors thus sought to develop novel molecules exhibiting activity comparable to IDC16, in terms of activity inhibiting HIV splicing, but while not exhibiting the characteristics of DNA intercalating agents.
  • 4-Chloropyridine 1 is obtained by neutralization of 4-chloropyridine hydrochloride with 10% NaOH as described in SCHMID & WOLKOFF (Canadian Journal of Chemistry, vol. 50, p. 1181-1187, 1972 ). 4-Chloropyridine 1 (15 mmol) is reacted in THF (250 ml) at -78 °C (nitrogen atmosphere) with 1.2 equivalents of lithium diisopropylamide (1.5 M solution in hexanes containing one equivalent of THF, ALDRICH) ( THRASHER et al., Heterocycles, vol. 67, p. 543-547, 2006 ).
  • compound 6 serves as a skeleton for the synthesis of stilbene analogues of IDC16, notably compounds 8a-j.
  • This reaction involves placing compound 6 , under the classic conditions of the WITTIG reaction (see for example GOPALSAMY et al., J. Med. Chem., vol. 47, p. 1893-1899, 2004 ), in contact with the required phosphonium salts obtained either commercially or prepared by reacting the required bromide derivative with triphenylphosphine.
  • the presence of E double bond geometry is deduced from the values of the 400 MHz 1H NMR spectrum.
  • 4-chloropyridine 1 is obtained by neutralization of 4-chloropyridine hydrochloride with 10% NaOH as described in SCHMID & WOLKOFF (Canadian Journal of Chemistry, vol. 50, p. 1181-1187, 1972 ).
  • 4-Chloropyridine 1 (15 mmol) is reacted in THF (250 ml) at -78 °C (nitrogen atmosphere) with 1.2 equivalents of lithium diisopropylamide (1.5 M solution in hexanes containing one equivalent of THF, ALDRICH) ( THRASHER et al., Heterocycles, vol. 67, p. 543-547, 2006 ).
  • Acid 5 is reacted in the presence of an excess of methyl iodide in DMF at 1000 °C for 2 h.
  • Compound 7 is then isolated as a colorless solid.
  • compound 7 serves as a skeleton for the synthesis of amide analogues of IDC16, notably compounds 9a-j.
  • This reaction involves placing compound 7 in contact with the required aromatic and heteroaromatic amines under classical conditions for forming peptide bonds.
  • compound 7 in solution in DMF containing N-methylmorpholine is reacted with isobutyl chloroformate (0 °C or room temperature, 1 hour), and compounds 9a-j are then isolated as colorless solids with yields of 60-90%.
  • These compounds are finally characterized by mass spectroscopy and 1H NMR (400 MHz).
  • Compound 12 is alkylated to obtain compounds 13a-j and 14a-j according to techniques well known to those skilled in the art (see in particular STARKOV, Tet. Letters, vol. 48, p. 1155-1157, 2007 ).
  • 4-Hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate 15 is prepared according to the protocol described in WALLACE et al. (J. Med. Chem., vol. 49, p. 441-444, 2006 ), then reacted with potassium trimethylsilanolate in THF for 4-5 hours at 20 °C ( MOTORINA et al., J. Am. Chem. Soc., vol. 23, p.
  • Compound 18 is alkylated to obtain compounds 19a-j and 20a-j again according to techniques well known to those skilled in the art (see notably STARKOV, Tet. Letters, vol. 48, p. 1155-1157, 2007 ).
  • Example 3 Selective inhibition of HIV-1 mRNA splicing ex vivo by compounds according to the present invention
  • p ⁇ PSP plasmid JACQUENET et al., J. Biol. Chem., vol. 276, p. 40464-40475, 2001 ), which contains the proviral HIV-1 genome with a deletion of nucleotides 1511 to 4550.
  • This p ⁇ PSP plasmid contains all HIV-1 splicing sites and the relative use of these various sites appears similar to that of the wild virus.
  • HeLa cells were cultivated in RPMI 1640 medium (GIBCO) supplemented with fetal calf serum on plates 3 cm in diameter (NUNC) to a confluence of 70-80%. These cells were then transfected with the p ⁇ PSP plasmid as described in JACQUENET et al . (2001).
  • HeLa cells transfected with p ⁇ PSP were then treated with various concentrations (1.5 ⁇ M or 3 ⁇ M) of the compounds described in example 2 or of IDC16 as a positive control.
  • concentrations 1.5 ⁇ M or 3 ⁇ M
  • Total cellular RNA was then extracted with the RNeasy kit (QIAGEN) while following the manufacturer's instructions. 4 ⁇ g of total RNA then underwent reverse transcription using the OMNISCRIPT REVERSE TRANSCRIPTASE kit (QIAGEN) while following the manufacturer's instructions. The mixture obtained was then aliquotted in 96-well plates and subjected to amplification using BSS sense primers (5'-GGCTTGCTGAAGCGCGCACGGCAAGAGG-3'; SEQ ID NO: 1), SJ4.7A anti-sense primers (5'- TTGGGAGGTGGGTTGCTTTGATAGAG-3'; SEQ ID NO: 2) and primers to amplify GAPDH as an internal control.
  • BSS sense primers 5'-GGCTTGCTGAAGCGCGCACGGCAAGAGG-3'; SEQ ID NO: 1
  • SJ4.7A anti-sense primers 5'- TTGGGAGGTGGGTTGCTTTGATAGAG-3'; SEQ ID NO: 2
  • BSS and SJ4.7A primers make it possible to amplify several isoforms resulting from various splices coding for viral proteins Nef, Rev, and Tat (JACQUENET et al ., cited above, 2001).
  • the PCR products were then analyzed by polyacrylamide gel electrophoresis after standardization with GAPDH ( SORET et al., Proc. Natl. Acad. Sci. U.S.A., vol. 102, p. 8764-8769, 2005 ).
  • Figure 1 shows the detail of a polyacrylamide gel obtained presenting the various isoforms obtained (Nef2, Rev1, Rev2, Nef3, Nef4, Nef5, Tat1 and Tat2) for the untreated cells (Clt) or treated with the compounds IDC16, C48, C49, C55 or C56.
  • the results show a dose-dependent reduction in the level of HIV-1 splicing products for the cells treated with compounds C48, C49, C55 and C56, a reduction comparable to that obtained in the presence of compound IDC16.
  • Example 4 Inhibition of HIV-1 production in infected peripheral blood mononuclear cells (PBMCs)
  • the first determination is that of the concentration of compound that exhibits the fewest side effects in terms of cell viability and progression of the cell cycle.
  • peripheral blood mononuclear cells of healthy donors are isolated by centrifugation on a FICOLL gradient. The cells are then cultivated to a density of 2.5 x 10 6 cells/ml with RPMI medium supplemented with 1% inactivated human AB serum, then incubated at 37 °C, 5% CO 2 for an additional hour. The peripheral blood mononuclear cells are then recovered and cultivated for two days in RPMI medium supplemented with 10% fetal calf serum.
  • PBMC peripheral blood mononuclear cells
  • PHA phytohemagglutinin A
  • PBMCs peripheral blood mononuclear cells
  • PHA and IL-2 peripheral blood mononuclear cells
  • IL-2 peripheral blood mononuclear cells
  • the cells are then cultivated for 14 days in the presence of the compounds described in example 2.
  • Viral replication is finally determined by quantifying protein p24 by the ELISA method.
  • cell viability is measured by exclusion with trypan blue in comparison with that of the untreated cells.
  • macrophages can be infected by the Ada-M R5 HIV strain and treated for 18 hours with various concentrations of the compounds described in example 2.
  • the culture medium is then eliminated and the cells washed with an abundance of PBS.
  • the cells are then cultivated under normal conditions.
  • the culture medium and the cells are then collected at days 4, 7 and 14.
  • virus replication is measured indirectly by determining the level of p24 antigen in both the culture supernatant and the cellular lysate by the ELISA method.
  • cell viability of the macrophages in the presence of the compounds of example 2 is measured as before.
  • HOS-CD4 + -CCR5 + cells to defective virions obtained by cotransfecting 293T cells with a plasmid encoding the R5 envelope of the AD8 strain and another plasmid containing the entire HIV-1 genome mutated in the envelope gene and harbouring a luciferase marker gene fused to nef ( Connor RI, Chen BK, Choe S, Landau NR. (1995) Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology 206: 935-944 .).
  • luciferase activity in cells infected with these virions reflect both the number of integrated proviruses and expression of multiply spliced species encoding nef/luc.
  • luciferase activity in HOS-CD4+-CCR5+ infected cells was measured.
  • the inhibitory effect could be smaller in this one-round infection assay than in other assays where several rounds of infection were carried out.
  • 12 show a luciferase inhibitory effect ranging between 30% up to 52%, which compound are listed in table II.
  • Peripheral blood mononuclear cells are treated or not treated with the compounds of example 2 and IDC16 as a positive control as described in example 3.
  • Preparation of total RNA for each culture condition followed by preparation of cDNA for each RNA sample is then carried out as described in example 3.
  • the mixture obtained is then aliquotted in 96-well plates and subjected to amplification using for each well a pair of sense and anti-sense primers specific to each isoform.
  • each isoform for the cells treated with the compounds of example 2 is then compared with that obtained for the cells treated with IDC16 and for the untreated cells.
  • RON is a tyrosine kinase receptor involved in tissue dissociation, cell mobility and invasion of the extracellular matrix
  • truncated isoform of the RON receptor is constitutively active due to the elimination of exon 11 sequences.
  • This truncated isoform is expressed strongly in breast cancer cells with high metastatic capacity and its expression is sufficient to activate epithelial-mesenchymal transition.
  • the figure 2 shows that the compounds MB260, FMB008 and FMMB22.3 strongly inhibit cell migration compared to negative control (CTL).
  • Duchenne muscular dystrophy presents many obstacles but also unparalleled prospect for correction by alternative splicing.
  • Duchenne muscular dystrophy results from mutations in the dystrophin gene, leading to the absence of its expression or to the expression of truncated proteins. More specifically, the majority of mutations in the dystrophin gene occur in the region encoding the spectrin-like central rod domain (see dia 1), which is largely dispensable.
  • Exon 51 is one of the most mutated exon of encoding the spectrin-like central rod domain in DMD patients. The skipping of exon 51 can generate a shortened but in-frame transcript, permitting translation of a partially functional dystrophin protein.
  • an animal model of Duchenne muscular dystrophy can be used, namely the mdx mouse. More specifically, mdx mice carry a stop codon mutation in exon 23 of the dystrophin gene which is responsible for completely extinguishing dystrophin expression. Thus, mdx mice can be treated with various concentrations of the compounds described in example 2 and then myoblast samples are taken from these mice to test these compounds for their capacity to induce exon 23 skipping in these cells.
  • Progeria is a rare (prevalence of approximately one in four to eight million births) and very severe developmental disorder characterized by the early appearance of certain pathologies usually developed during physiological aging, such as atherosclerosis, insulin resistant type II diabetes, cataracts, osteoporosis and aging of the skin. Analysis of this pathology has shown that it results from abnormal expression of the LMNA gene associated with its abnormal splicing. Astonishingly, this same aberrant splicing of the LMNA gene has been found in healthy elderly subjects not carrying the mutation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Oncology (AREA)
  • Diabetes (AREA)
  • Virology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Psychiatry (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Reproductive Health (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Psychology (AREA)
  • Dermatology (AREA)
  • Ophthalmology & Optometry (AREA)

Claims (4)

  1. Composé choisi dans le groupe comprenant :
    • N-(3-diméthylaminopropyl)-3-(4-trifluorométhoxyphénylamino)benzamide,
    • 4-(4-méthoxyphénylamino)-3-méthyl-N-(3-méthylbutyl)benzamide,
    • 3-méthyl-N-(3-méthylbutyl)-4-(4-trifluorométhoxyphénylamino)benzamide,
    • N-(2-diméthylaminoéthyl)-2-(4-trifluorométhoxyphénylamino)benzamide,
    • N-(2-(diéthylaminoéthyl)-2-(4-trifluorométhoxyphénylamino)benzamide,
    • N-(2-diéthylaminopropyl)-2-(4-trifluorométhoxyphénylamino)benzamide,
    • N-(3-imidazol-1-ylpropyl)-2-(4-méthoxyphénylamino)benzamide,
    • N-(3-imidazol-1-ylpropyl)-2-(4-trifluorométhoxyphénylamino)benzamide,
    • N-(2-diméthylaminoéthyl)-4-(4-trifluorométhoxyphénylamino)benzamide,
    • N-(2-diméthylaminoéthyl)-4-(4-méthoxyphénylamino)-3-méthylbenzamide,
    • N-(3-diéthylaminopropyl)-4-(4-méthoxyphénylamino)-3-méthylbanzamide,
    • N-(3-diéthylaminopropyl)-3-méthyl-4-(4-trifluorométhoxyphénylamino)benzamide,
    • N-(2-diméthylaminoéthyl)-3-méthyl-4-(4-trifluorométhoxyphénylamino)benzamide,
    • [4-(5-chloro-1H-imidazol-2-yl)-2-méthylphényl]-(4-méthoxyphényl)amine,
    • N-(2-diméthylaminoéthyl)-2-(4-méthoxyphénylamino)benzamide,
    • N-(3-imidazol-1-ylpropyl)-4-(4-trifluorométhoxyphénylamino)benzamide,
    • N-(2-diéthylaminoéthyl)-2-(4-méthoxyphénylamino)benzamide,
    • N-(3-diméthylaminopropyl)-3-(4-méthoxyphénylamino)benzamide et
    • N-(3-diméthylaminopropyl)-2-(4-méthoxyphénylamino)benzamide.
  2. Composition pharmaceutique, caractérisée en ce qu'elle comprend au moins un composé selon la revendication 1 et, éventuellement, un support pharmaceutiquement acceptable.
  3. Utilisation d'au moins un composé selon la revendication 1 dans la préparation d'un médicament pour traiter, chez un sujet, une maladie liée au processus d'épissage d'ARN pré-messagers dans la cellule, caractérisée en ce que ladite maladie est une maladie d'origine virale, préférablement le sida.
  4. Composé selon la revendication 1 pour une utilisation dans le traitement, chez un sujet, d'une maladie liée au procédé d'épissage d'ARN pré-messagers dans la cellule, caractérisée en ce que ladite maladie est une maladie d'origine virale, préférablement le sida.
EP09700499.8A 2008-01-10 2009-01-12 Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage Active EP2235000B1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP19164367.5A EP3536691B1 (fr) 2008-01-10 2009-01-12 Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage
PL09700499T PL2235000T3 (pl) 2008-01-10 2009-01-12 Cząsteczki chemiczne hamujące mechanizm splicingu do leczenia chorób wynikających z nieprawidłowości splicingu
HRP20201369TT HRP20201369T1 (hr) 2008-01-10 2020-08-28 Kemijske molekule koje inhibiraju mehanizam prekrajanja za lječenje bolesti koje proizlaze iz anomalija prekrajanja

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0850144A FR2926297B1 (fr) 2008-01-10 2008-01-10 Molecules chimiques inhibitrices du mecanisme d'epissage pour traiter des maladies resultant d'anomalies d'epissage.
PCT/EP2009/050280 WO2009087238A2 (fr) 2008-01-10 2009-01-12 Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage

Related Child Applications (2)

Application Number Title Priority Date Filing Date
EP19164367.5A Division-Into EP3536691B1 (fr) 2008-01-10 2009-01-12 Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage
EP19164367.5A Division EP3536691B1 (fr) 2008-01-10 2009-01-12 Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage

Publications (2)

Publication Number Publication Date
EP2235000A2 EP2235000A2 (fr) 2010-10-06
EP2235000B1 true EP2235000B1 (fr) 2020-06-17

Family

ID=39720243

Family Applications (2)

Application Number Title Priority Date Filing Date
EP09700499.8A Active EP2235000B1 (fr) 2008-01-10 2009-01-12 Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage
EP19164367.5A Active EP3536691B1 (fr) 2008-01-10 2009-01-12 Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP19164367.5A Active EP3536691B1 (fr) 2008-01-10 2009-01-12 Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage

Country Status (12)

Country Link
US (4) US8604063B2 (fr)
EP (2) EP2235000B1 (fr)
JP (1) JP5784909B2 (fr)
CN (3) CN104130242B (fr)
CA (5) CA3072245C (fr)
DK (1) DK2235000T3 (fr)
ES (2) ES2934810T3 (fr)
FR (4) FR2926297B1 (fr)
HR (1) HRP20201369T1 (fr)
PL (1) PL2235000T3 (fr)
PT (1) PT2235000T (fr)
WO (1) WO2009087238A2 (fr)

Families Citing this family (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8367669B2 (en) 2005-06-15 2013-02-05 Vanderbilt University Inhibitors of hemeprotein-catalyzed lipid peroxidation
US9133212B1 (en) 2005-06-15 2015-09-15 Vanderbilt University Inhibitors of hemeprotein-catalyzed lipid peroxidation
FR2926297B1 (fr) 2008-01-10 2013-03-08 Centre Nat Rech Scient Molecules chimiques inhibitrices du mecanisme d'epissage pour traiter des maladies resultant d'anomalies d'epissage.
AR077033A1 (es) 2009-06-11 2011-07-27 Hoffmann La Roche Compuestos inhibidores de las quinasas de janus y su uso en el tratamiento de enfermedades inmunologicas
CN106928205B (zh) 2009-06-12 2019-09-24 Abivax公司 用于治疗过早衰老和尤其是早衰的化合物
US10253020B2 (en) 2009-06-12 2019-04-09 Abivax Compounds for preventing, inhibiting, or treating cancer, AIDS and/or premature aging
EP2266972A1 (fr) * 2009-06-12 2010-12-29 Splicos Nouvelles molécules chimiques qui inhibent le mécanisme d'épissage pour le traitement de maladies résultant d'anomalies d'épissage
JP5819305B2 (ja) * 2009-10-13 2015-11-24 リガンド・ファーマシューティカルズ・インコーポレイテッド 造血成長因子模倣小分子化合物およびそれらの使用
US9241929B2 (en) 2010-06-28 2016-01-26 Masatoshi Hagiwara Prophylactic or ameliorating agent for genetic diseases
EP2465502A1 (fr) 2010-12-15 2012-06-20 Société Splicos Composés utiles pour traiter le SIDA
US8754114B2 (en) 2010-12-22 2014-06-17 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
EP2505198A1 (fr) 2011-04-01 2012-10-03 Société Splicos Composés pour leur utilisation en tant qu'agents thérapeutiques affectant l'expression et/ou l'activité de p53
FR2987627B1 (fr) 2012-03-05 2016-03-18 Splicos Utilisation de rbm39 comme biomarqueur
PL3176170T3 (pl) 2012-06-13 2019-05-31 Incyte Holdings Corp Podstawione związki tricykliczne jako inhibitory fgfr
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
EP2712862A1 (fr) * 2012-09-28 2014-04-02 Splicos Nouveaux composés anti-invasifs
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
EP2757161A1 (fr) 2013-01-17 2014-07-23 Splicos miRNA-124 comme biomarqueur de l'infection virale
ITMI20130444A1 (it) * 2013-03-22 2014-09-23 S B M Science Of Biology In Medici Ne Srl Composto di inclusione comprendente adjudin [1-(2,4-diclorobenzil) - 1h-indazolo-3-carboidrazide] e ciclodestrina, sua preparazione e utilizzo.
CA2909207C (fr) 2013-04-19 2021-11-02 Incyte Corporation Heterocycles bicycliques utilises en tant qu'inhibiteurs de fgfr
HRP20211839T1 (hr) 2013-07-05 2022-03-04 Abivax Biciklički spojevi korisni za liječenje bolesti uzrokovanih retrovirusima
JP6637890B2 (ja) * 2013-12-24 2020-01-29 オンコターティス インコーポレイテッドＯｎｃｏｔａｒｔｉｓ， Ｉｎｃ． ベンズアミド及びニコチンアミド化合物及びこれを使用する方法
EP2974729A1 (fr) 2014-07-17 2016-01-20 Abivax Dérivés de quinoléine utilisés dans le traitement de maladies inflammatoires
EP3189070A4 (fr) 2014-08-04 2018-06-27 Drexel University Nouveaux composés et procédés pour traiter ou atténuer un trouble ou une maladie à médiation par il-1r au moyen de ces composés
JP6837429B2 (ja) * 2014-08-11 2021-03-03 ザ ボード オブ リージェンツ オブ ザ ユニバーシティー オブ テキサス システム Ｃｒｉｓｐｒ／ｃａｓ９媒介遺伝子編集による筋ジストロフィーの予防
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
EP3617205B1 (fr) 2015-02-20 2021-08-04 Incyte Corporation Hétérocycles bicycliques utilisés comme inhibiteurs des fgfr
MA41551A (fr) 2015-02-20 2017-12-26 Incyte Corp Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
EP3617311A4 (fr) 2017-03-30 2021-04-21 Kyoto University Procédé pour induire un saut d'exon par édition génomique
AR111960A1 (es) 2017-05-26 2019-09-04 Incyte Corp Formas cristalinas de un inhibidor de fgfr y procesos para su preparación
WO2019199972A1 (fr) * 2018-04-10 2019-10-17 Skyhawk Therapeutics, Inc. Composés pour le traitement d'un cancer
WO2019213506A1 (fr) 2018-05-04 2019-11-07 Incyte Corporation Sels d'un inhibiteur de fgfr
CA3099287A1 (fr) 2018-05-04 2019-11-07 Incyte Corporation Formes solides d'un inhibiteur de fgfr et leurs procedes de preparation
EP3594205A1 (fr) * 2018-07-09 2020-01-15 Abivax Dérivés phényl-n-aryl pour traiter une infection par le virus d'arn
EP3669873A1 (fr) 2018-12-20 2020-06-24 Abivax Dérivés de quinoline destinés à être utilisés dans le traitement de maladies inflammatoires
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
CN110172037A (zh) * 2019-07-01 2019-08-27 华北理工大学 一种含吡啶结构的苯乙烯基吡啶化合物、制备方法及其制备抗肿瘤药物的应用
WO2021007269A1 (fr) 2019-07-09 2021-01-14 Incyte Corporation Hétérocycles bicycliques en tant qu'inhibiteurs de fgfr
CU20220002A7 (es) * 2019-07-19 2022-08-09 Abivax Derivados de aril-n-arilo para tratar una infección por virus de ácido ribonucleico (arn)
EP3848356A1 (fr) * 2020-01-07 2021-07-14 Abivax Dérivés aryl-n-aryl pour traiter une infection par le virus d'arn
KR20220100879A (ko) 2019-10-14 2022-07-18 인사이트 코포레이션 Fgfr 저해제로서의 이환식 헤테로사이클
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
EP4069696A1 (fr) 2019-12-04 2022-10-12 Incyte Corporation Hétérocycles tricycliques en tant qu'inhibiteurs de fgfr
MX2022006691A (es) 2019-12-04 2022-09-19 Incyte Corp Derivados de un inhibidor de receptores del factor de crecimiento de fibroblastos (fgfr).
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
WO2022261160A1 (fr) 2021-06-09 2022-12-15 Incyte Corporation Hétérocycles tricycliques en tant qu'inhibiteurs de fgfr
AU2022388884A1 (en) 2021-11-15 2024-05-30 Pi Industries Ltd. Bicyclic heteroaromatic compounds and their use as pest control agents
WO2023173081A2 (fr) * 2022-03-11 2023-09-14 The Johns Hopkins University Ciblage d'une alpha kinase du facteur d'initiation eucaryote 2 pour réguler la traduction sous contrainte
WO2023218245A1 (fr) * 2022-05-13 2023-11-16 Voronoi Inc. Composés dérivés d'hétéroaryle et composition pharmaceutique les comprenant

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2274620A (en) * 1940-01-02 1942-02-24 S M A Corp Substituted aryl amides of pyridine carboxylic acid
US4001416A (en) * 1974-04-09 1977-01-04 Basf Aktiengesellschaft Certain fungicidal pyridines
US4855308A (en) * 1987-12-04 1989-08-08 Warner-Lambert Company Method of treating senile cognitive decline with N'-substituted aminopyridine adrenergic agents
US6268387B1 (en) * 1997-12-23 2001-07-31 Warner-Lambert Company Thiourea and benzamide compounds, compositions and methods of treating or preventing inflammatory diseases and atherosclerosis
US20030225106A1 (en) * 2001-01-12 2003-12-04 Amgen Inc. Substituted alkylamine derivatives and methods of use
US20040171833A1 (en) * 1998-07-10 2004-09-02 Buchwald Stephen L. Ligands for metals and improved metal-catalyzed processes based thereon
FR2859475A1 (fr) * 2003-09-04 2005-03-11 Centre Nat Rech Scient Utilisation de composes derives d'ellipticine et d'aza-ellipticine pour la preparation d'un medicament utile pour le traitement de maladies genetiques resultant de l'alteration des processus d'epissage
FR2859474A1 (fr) * 2003-09-04 2005-03-11 Centre Nat Rech Scient Utilisation de composes derives d'indole pour la preparation d'un medicament utile pour le traitement de maladies genetiques resultant de l'alteration des processus d'epissage
WO2007096647A2 (fr) * 2006-02-27 2007-08-30 Sterix Limited Composé

Family Cites Families (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR400973A (fr) 1909-03-19 1909-08-13 Jean Victor Massillon Nouveau sertisseur à main pour la fabrication des cartouches
DE374291C (de) * 1914-03-24 1923-04-21 Alexei Ewgenjewitsch Tschitsch Verfahren zur Darstellung von Aminosubstitutionsprodukten der Pyridin- und Chinolinreihe
US2671805A (en) 1952-07-02 1954-03-09 Searle & Co Basically substituted o-arylamino-benzamides
DE1168435B (de) * 1961-12-09 1964-04-23 Kali Chemie Ag Verfahren zur Herstellung von 4-Oxo-3, 4-dihydrochinazolinen
NL132603C (fr) 1964-08-29
US3409668A (en) 1964-11-07 1968-11-05 Palazzo Giuseppe Substituted anthranilamides and process for the preparation thereof
GB1318291A (en) * 1970-04-15 1973-05-23 Shell Int Research Carboxamide derivatives and fungicidal compositions containing them
JPS5095285A (fr) 1973-12-26 1975-07-29
JPS52133939A (en) * 1976-04-30 1977-11-09 Ihara Chem Ind Co Ltd Preparation of 2-substituted benzanilides
FR2436786A1 (fr) 1978-09-21 1980-04-18 Anvar Nouveaux derives des pyrido (4,3-b) carbazoles (ellipticines), substitues en position 1 par une chaine polyaminee, leur obtention et leur application a titre de medicaments
US4510139A (en) * 1984-01-06 1985-04-09 Sterling Drug Inc. Substituted aminobenzamides and their use as agents which inhibit lipoxygenase activity
JPS62158252A (ja) * 1985-12-28 1987-07-14 Kirin Brewery Co Ltd ４−アミノピリジンベンズアミド誘導体
DE3819025A1 (de) * 1987-09-01 1989-05-24 Fuji Photo Film Co Ltd Verfahren zur herstellung von alkoxybenzolverbindungen
FR2627493B1 (fr) 1988-02-23 1991-10-31 Sanofi Sa Procede de preparation de derives d'isoquinoleine
FR2645861A1 (fr) 1989-04-17 1990-10-19 Inst Nat Sante Rech Med Utilisation de dipyrido (4,3-b) (3,4-f) indoles pour la preparation de medicaments utiles pour le traitement du sida
US5579033A (en) * 1992-05-20 1996-11-26 International Business Machines Corporation Pointing device for retrofitting onto the keyboard of an existing computer system
GB9715584D0 (en) 1997-07-23 1997-10-01 Eisai Co Ltd Compounds
ATE360634T1 (de) * 1998-07-10 2007-05-15 Massachusetts Inst Technology Ligande für metalle und verbesserte metall- katalysierte verfahren, die darauf basieren
FR2787444B1 (fr) 1998-12-22 2001-02-09 Rhodia Chimie Sa Composition et procede d'inhibition de la polymerisation radicalaire de monomeres aliphatiques a insaturation ethylenique
CA2358091A1 (fr) * 1998-12-23 2000-07-06 Eli Lilly And Company Amides antithrombotiques
FR2789576B1 (fr) * 1999-02-16 2002-04-26 Oreal Composition de teinture d'oxydation des fibres keratiniques et procede de teinture mettant en oeuvre cette composition
US7101948B2 (en) 2001-12-21 2006-09-05 Air Products And Chemicals, Inc. Stabilizers to inhibit the polymerization of substituted cyclotetrasiloxane
FR2836917B1 (fr) * 2002-03-11 2006-02-24 Lipha Derives nitroso de la diphenylamine, compositions pharmaceutiques les contenant en tant que medicaments utilisables dans le traitement des pathologies caracterisees par une situation de stress oxydatif
US20060040931A1 (en) * 2002-12-06 2006-02-23 Toray Industries, Inc. Benzomorpholine derivatives
WO2004052939A2 (fr) * 2002-12-09 2004-06-24 Massachusetts Institute Of Technology Ligands pour metaux et processus a catalyse par metaux ameliores bases sur ces ligands
AU2003299750A1 (en) 2002-12-20 2004-07-22 Irm Llc Differential tumor cytotoxocity compounds and compositions
WO2005025498A2 (fr) * 2003-09-08 2005-03-24 Corus Pharma Acetanilides et benzamides substitues utilises dans le traitement de l'asthme et des inflammations pulmonaires
FR2862964B1 (fr) 2003-11-27 2006-12-29 Merck Sante Sas Derives de la diphenylamine.
FR2862965B1 (fr) * 2003-11-27 2007-09-07 Merck Sante Sas Nouveaux derives de phenoxyacetamides et leur utilisation pour la preparation de diphenylamides.
TWI380975B (zh) 2004-03-25 2013-01-01 Otsuka Pharma Co Ltd 製造胺基酚類化合物的方法
AU2006210537A1 (en) 2005-02-02 2006-08-10 Fox Chase Cencer Center Amine derivative containing compositions and methods for the treatment of viral infections related to the etiology of cancer
CN101243166B (zh) 2005-06-13 2013-06-12 朗盛橡胶有限公司 包括酰胺化或酰亚胺化聚合物的添加剂组合物
US20090118135A1 (en) 2007-06-08 2009-05-07 The Burnham Institute Methods and compounds for regulating apoptosis
FR2926297B1 (fr) 2008-01-10 2013-03-08 Centre Nat Rech Scient Molecules chimiques inhibitrices du mecanisme d'epissage pour traiter des maladies resultant d'anomalies d'epissage.
EP2712862A1 (fr) 2012-09-28 2014-04-02 Splicos Nouveaux composés anti-invasifs

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2274620A (en) * 1940-01-02 1942-02-24 S M A Corp Substituted aryl amides of pyridine carboxylic acid
US4001416A (en) * 1974-04-09 1977-01-04 Basf Aktiengesellschaft Certain fungicidal pyridines
US4855308A (en) * 1987-12-04 1989-08-08 Warner-Lambert Company Method of treating senile cognitive decline with N'-substituted aminopyridine adrenergic agents
US6268387B1 (en) * 1997-12-23 2001-07-31 Warner-Lambert Company Thiourea and benzamide compounds, compositions and methods of treating or preventing inflammatory diseases and atherosclerosis
US20040171833A1 (en) * 1998-07-10 2004-09-02 Buchwald Stephen L. Ligands for metals and improved metal-catalyzed processes based thereon
US20030225106A1 (en) * 2001-01-12 2003-12-04 Amgen Inc. Substituted alkylamine derivatives and methods of use
FR2859475A1 (fr) * 2003-09-04 2005-03-11 Centre Nat Rech Scient Utilisation de composes derives d'ellipticine et d'aza-ellipticine pour la preparation d'un medicament utile pour le traitement de maladies genetiques resultant de l'alteration des processus d'epissage
FR2859474A1 (fr) * 2003-09-04 2005-03-11 Centre Nat Rech Scient Utilisation de composes derives d'indole pour la preparation d'un medicament utile pour le traitement de maladies genetiques resultant de l'alteration des processus d'epissage
WO2007096647A2 (fr) * 2006-02-27 2007-08-30 Sterix Limited Composé

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
ALFONSO R GENNARO: "Pyrido[3,2-b][1,4]benzothiazine(1-azaphenothiazine)", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 24, 1 January 1959 (1959-01-01), pages 1156 - 1157, XP002499121, ISSN: 0022-3263, DOI: 10.1021/JO01090A625 *
BERTHIOL F ET AL: "Heck reaction with heteroaryl halides in the presence of a palladium-tetraphosphine catalyst", TETRAHEDRON LETTERS, ELSEVIER LTD, AMSTERDAM, NL, vol. 43, no. 32, 5 August 2002 (2002-08-05), pages 5625 - 5628, XP004371578, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(02)01109-7 *
BERTHIOL F ET AL: "Heck reaction with heteroaryl halides in the presence of a palladium-tetraphosphine catalyst", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 43, no. 32, 5 August 2002 (2002-08-05), pages 5625 - 5628, XP004371578, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(02)01109-7 *
C. CATIVIELA ET AL: "A convenient synthesis of N -aryl-1,2-dihydro-2-oxo-3-pyridinecarbox-amides, N -aryl- N -methyl-1,2-dihydro-2-oxo-3-pyridinecarboxamides and their 1-methyl ( O -methyl)-derivatives", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 19, no. 5, 1 September 1982 (1982-09-01), US, pages 1093 - 1097, XP055315726, ISSN: 0022-152X, DOI: 10.1002/jhet.5570190522 *
CHEUK-MAN LEE: "Synthesis of 1-methyl-3H-1,4-benzodiazepline-2,5 (1H,4H) -dione and derivatives", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 1, no. 5, 1 December 1964 (1964-12-01), US, pages 235 - 238, XP055316174, ISSN: 0022-152X, DOI: 10.1002/jhet.5570010504 *
COYNE W E ET AL: "3,4-DIHYDRO-2(1H)-QUINAZOLINONES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 11, no. 6, 1 January 1968 (1968-01-01), pages 1208 - 1213, XP000909664, ISSN: 0022-2623, DOI: 10.1021/JM00312A022 *
DATABASE CAPLUS, [online] 25 August 1965 (1965-08-25), "Aminopyridines", XP002499122, retrieved from CAPLUS Database accession no. 1966-412224 *
EITER K ET AL: "über das 9-methyl-3-carbolin und das 6-methyl-3-carbolin", MONATSHEFTE FÜR CHEMIE = CHEMICAL MONTHLY, SPRINGER VIENNA, VIENNA, vol. 81, 1 January 1950 (1950-01-01), pages 404 - 413, XP002499120, ISSN: 0026-9247, DOI: 10.1007/BF00903042 *
HUANG X ET AL: "Expanding Pd-Catalyzed C-N Bond-Forming Processes: The First Amidation of Aryl Sulfonates, Aqueous Amination, and Complementarity with Cu-Catalyzed Reactions", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, US, vol. 125, no. 22, 1 January 2003 (2003-01-01), pages 6653 - 6655, XP002366815, ISSN: 0002-7863, DOI: 10.1021/JA035483W *
JOZWIAK: "Application of organolithium and related agents in synthesis, 30. Behaviour of N-pyridylbenzamides versus benzanilides in the ortho-directed lithiation of masked aromatic carboxylic acids", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 15, 1 January 2004 (2004-01-01), pages 3254 - 3261, XP002337206, ISSN: 1434-193X, DOI: 10.1002/EJOC.200400156 *
JUSTIN T. ERNST ET AL: "Design and Application of an [alpha]-Helix-Mimetic Scaffold Based on an Oligoamide-Foldamer Strategy: Antagonism of the Bak BH3/Bcl-xL Complex", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 1,4,642, no. 5, 3 February 2003 (2003-02-03), DE, pages 535 - 539, XP055315829, ISSN: 1433-7851, DOI: 10.1002/anie.200390154 *
JYE-SHANE YANG ET AL: "Meta Conjugation Effect on the Torsional Motion of Aminostilbenes in the Photoinduced Intramolecular Charge-Transfer State", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 129, no. 43, 1 October 2007 (2007-10-01), US, pages 13183 - 13192, XP055315882, ISSN: 0002-7863, DOI: 10.1021/ja0741022 *
MAJIMA T ET AL: "Cis-Trans Isomerization and Oxidation of Radical Cations of Stilbene Derivatives", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 61, no. 22, 1 January 1996 (1996-01-01), pages 7793 - 7800, XP002163396, ISSN: 0022-3263, DOI: 10.1021/JO960598M *
MAJIMA T ET AL: "Cis-Trans Isomerization and Oxidation of Radical Cations of Stilbene Derivatives", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 61, no. 22, 1 January 1996 (1996-01-01), pages 7793 - 7800, XP002163396, ISSN: 0022-3263, DOI: 10.1021/JO960598M *
NETAI C SINGHA ET AL: "1H and 13C NMR spectral studies of conformation of some N-(2-pyridinyl)-3-pyridinecarboxamides", JOURNAL OF MOLECULAR STRUCTURE, ELSEVIER, AMSTERDAM, NL, vol. 1,4,6449, no. 1, 4 August 1998 (1998-08-04), pages 91 - 98, XP002711896, ISSN: 0022-2860 *
NORTON P PEET ET AL: "A novel oxanide rearrangement", JOURNAL OF HETEROCYCLIC CHEMISTRY, WILEY-BLACKWELL PUBLISHING, INC, US, vol. 17, 1 January 1980 (1980-01-01), pages 1513 - 1518, XP002499119, ISSN: 0022-152X, DOI: 10.1002/JHET.5570170731 *
SHANKARAN K ET AL: "Silicon in benzamide directed ortho methalation formation and reactions of benzamide benzynes", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 25, no. 27, 1 January 1984 (1984-01-01), pages 2827 - 2830, XP002499118, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(01)81301-0 *
SIGOVA V I ET AL: "Synthesis and biological activity of the aryl amides of 2-methylnicotinic and 2-phenylindolisine-8-carboxylic acids", PHARMACEUTICAL CHEMISTRY JOURNAL, SPRINGER NEW YORK LLC, US, vol. 19, no. 3, 1 January 1985 (1985-01-01), pages 174 - 177, XP002711898, ISSN: 0091-150X *
SORENSON R J: "Selective N-arylation of aminobenzanilides under mild conditions using triarylbismuthanes", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 65, 21 October 2000 (2000-10-21), pages 7747 - 7749, XP002398734, ISSN: 0022-3263, DOI: 10.1021/JO000614M *
TAKASHI IKAWA ET AL: "Pd-Catalyzed Amidation of Aryl Chlorides Using Monodentate Biaryl Phosphine Ligans: a Kinetic, Computational, and Synthetic Investigation", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,, vol. 129, no. 43, 1 January 2007 (2007-01-01), pages 13001 - 13007, XP002551206, DOI: 10.1021/JA0717414 *
V. P. CHESNOKOV ET AL: "Investigation of naphthyridines", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, vol. 1,4,610, no. 2, 1 February 1974 (1974-02-01), US, pages 217 - 218, XP055315871, ISSN: 0009-3122, DOI: 10.1007/BF00487788 *
WARD Y D ET AL: "Solid Phase Synthesis of Aryl Amines Via Palladium Catalyzed Amination of Resin-Bound Aromatic Bromides", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 37, no. 39, 23 September 1996 (1996-09-23), pages 6993 - 6996, XP004030807, ISSN: 0040-4039, DOI: 10.1016/0040-4039(96)01566-3 *

Also Published As

Publication number Publication date
JP2011509280A (ja) 2011-03-24
DK2235000T3 (da) 2020-09-07
CA2946329A1 (fr) 2009-07-16
FR2983199B1 (fr) 2015-09-25
US8604063B2 (en) 2013-12-10
EP2235000A2 (fr) 2010-10-06
CA2946326C (fr) 2019-02-19
CA2946329C (fr) 2020-09-01
CA3072245A1 (fr) 2009-07-16
PT2235000T (pt) 2020-09-03
CN101965341B (zh) 2014-07-16
CA2946336A1 (fr) 2009-07-16
CN104130242A (zh) 2014-11-05
FR2983200A1 (fr) 2013-05-31
JP5784909B2 (ja) 2015-09-24
US20190022037A1 (en) 2019-01-24
CN104086482B (zh) 2017-10-13
ES2934810T3 (es) 2023-02-27
US20160166519A1 (en) 2016-06-16
FR2983196B1 (fr) 2015-12-11
WO2009087238A3 (fr) 2010-09-16
WO2009087238A2 (fr) 2009-07-16
FR2926297A1 (fr) 2009-07-17
US10654813B2 (en) 2020-05-19
CA2711652C (fr) 2016-12-06
CN101965341A (zh) 2011-02-02
PL2235000T3 (pl) 2021-05-17
ES2816178T3 (es) 2021-03-31
HRP20201369T1 (hr) 2020-11-27
FR2926297B1 (fr) 2013-03-08
CA2711652A1 (fr) 2009-07-16
FR2983199A1 (fr) 2013-05-31
CA3072245C (fr) 2022-10-04
US20140155436A1 (en) 2014-06-05
EP3536691B1 (fr) 2022-10-05
US10130595B2 (en) 2018-11-20
CA2946326A1 (fr) 2009-07-16
WO2009087238A9 (fr) 2010-02-25
US9233931B2 (en) 2016-01-12
US20110053975A1 (en) 2011-03-03
EP3536691A1 (fr) 2019-09-11
FR2983196A1 (fr) 2013-05-31
CN104086482A (zh) 2014-10-08
CA2946336C (fr) 2019-02-19
FR2983200B1 (fr) 2015-09-25
CN104130242B (zh) 2016-10-05

Similar Documents

Publication Publication Date Title
US10654813B2 (en) Chemical molecules that inhibit the slicing mechanism for treating diseases resulting from splicing anomalies
US10017498B2 (en) Compounds useful for treating AIDS

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20100708

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA RS

R17D Deferred search report published (corrected)

Effective date: 20100916

DAX Request for extension of the european patent (deleted)
RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: UNIVERSITE DE MONTPELLIER

Owner name: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS

Owner name: INSTITUT CURIE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

PUAG Search results despatched under rule 164(2) epc together with communication from examining division

Free format text: ORIGINAL CODE: 0009017

17Q First examination report despatched

Effective date: 20161114

17Q First examination report despatched

Effective date: 20161118

B565 Issuance of search results under rule 164(2) epc

Effective date: 20161118

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20200205

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602009062247

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1281142

Country of ref document: AT

Kind code of ref document: T

Effective date: 20200715

REG Reference to a national code

Ref country code: FI

Ref legal event code: FGE

Ref country code: HR

Ref legal event code: TUEP

Ref document number: P20201369T

Country of ref document: HR

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Ref document number: 2235000

Country of ref document: PT

Date of ref document: 20200903

Kind code of ref document: T

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20200826

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Effective date: 20200903

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20200402565

Country of ref document: GR

Effective date: 20201014

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200617

REG Reference to a national code

Ref country code: NO

Ref legal event code: T2

Effective date: 20200617

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: HR

Ref legal event code: T1PR

Ref document number: P20201369

Country of ref document: HR

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200617

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200917

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20201369

Country of ref document: HR

Payment date: 20210107

Year of fee payment: 13

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200617

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200617

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200617

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200617

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602009062247

Country of ref document: DE

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2816178

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20210331

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20210318

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20201369

Country of ref document: HR

Payment date: 20220111

Year of fee payment: 14

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20201369

Country of ref document: HR

Payment date: 20221229

Year of fee payment: 15

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20090112

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200617

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200617

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20201369

Country of ref document: HR

Payment date: 20240125

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20240126

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20240126

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20240129

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IS

Payment date: 20240125

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20240223

Year of fee payment: 16

Ref country code: IE

Payment date: 20240126

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20240126

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MC

Payment date: 20240124

Year of fee payment: 16

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200617

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FI

Payment date: 20240125

Year of fee payment: 16

Ref country code: DE

Payment date: 20240130

Year of fee payment: 16

Ref country code: GB

Payment date: 20240130

Year of fee payment: 16

Ref country code: PT

Payment date: 20240125

Year of fee payment: 16

Ref country code: CH

Payment date: 20240212

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20240201

Year of fee payment: 16

Ref country code: SE

Payment date: 20240126

Year of fee payment: 16

Ref country code: PL

Payment date: 20240125

Year of fee payment: 16

Ref country code: NO

Payment date: 20240129

Year of fee payment: 16

Ref country code: IT

Payment date: 20240129

Year of fee payment: 16

Ref country code: HR

Payment date: 20240125

Year of fee payment: 16

Ref country code: FR

Payment date: 20240131

Year of fee payment: 16

Ref country code: DK

Payment date: 20240126

Year of fee payment: 16

Ref country code: BE

Payment date: 20240125

Year of fee payment: 16